Glykofrydes D, Niphuis H, Kuhn E M, Rosenwirth B, Heeney J L, Bruder J, Niedobitek G, Müller-Fleckenstein I, Fleckenstein B, Ensser A
Institut für Klinische und Molekulare Virologie der Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
J Virol. 2000 Dec;74(24):11919-27. doi: 10.1128/jvi.74.24.11919-11927.2000.
Apoptosis of infected cells is an important host defense mechanism, and many viruses have exploited antiapoptotic proteins that interfere with crucial cellular pathways. Viral FLICE inhibitory proteins (vFLIPs) are encoded by rhadinoviruses like herpesvirus saimiri, the related Kaposi's sarcoma-associated herpesvirus-human herpesvirus 8 (KSHV/HHV8), and the poxvirus responsible for molluscum contagiosum. The vFLIPs can block the interaction of the death receptor-adapter complex with the cellular effector FLICE (caspase-8), and this prevents the initiation of the downstream caspase cascade. KSHV/HHV8 vFLIP overexpression can confer resistance to T-cell-mediated apoptosis and acts as a tumor progression factor in a murine B-cell lymphoma model. To analyze the function of herpesvirus vFLIPs in the genetic background of the virus and in a model for viral pathogenesis, we deleted the vFLIP gene (open reading frame 71) from the genome of herpesvirus saimiri strain C488. The viral deletion mutant was viable and replicated like the wild-type virus. An antiapoptotic effect could be attributed to the vFLIP gene, but we also show that the vFLIP gene of herpesvirus saimiri is dispensable for viral transformation of T cells in vitro and for pathogenicity in cottontop tamarins in vivo.
受感染细胞的凋亡是一种重要的宿主防御机制，许多病毒利用抗凋亡蛋白来干扰关键的细胞通路。病毒FLICE抑制蛋白（vFLIPs）由诸如猴疱疹病毒等γ疱疹病毒编码，相关的卡波西肉瘤相关疱疹病毒——人类疱疹病毒8型（KSHV/HHV8），以及引起传染性软疣的痘病毒。vFLIPs可阻断死亡受体衔接蛋白复合物与细胞效应因子FLICE（半胱天冬酶-8）的相互作用，从而阻止下游半胱天冬酶级联反应的启动。KSHV/HHV8 vFLIP的过表达可赋予对T细胞介导的凋亡的抗性，并在小鼠B细胞淋巴瘤模型中作为肿瘤进展因子发挥作用。为了分析疱疹病毒vFLIPs在病毒遗传背景以及病毒致病模型中的功能，我们从猴疱疹病毒C488株的基因组中删除了vFLIP基因（开放阅读框71）。病毒缺失突变体是有活力的，并且像野生型病毒一样复制。抗凋亡作用可归因于vFLIP基因，但我们还表明，猴疱疹病毒的vFLIP基因对于体外T细胞的病毒转化以及体内绢毛猴的致病性来说并非必需。
